Xuequn Zhang

Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem in recent decades. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD. Therefore, understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation. This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.

Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: enoyl-coenzyme a hydratase down-regulation exacerbates hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem that can progress to end‐stage liver disease. A high‐fat diet (HFD) may promote the development of NAFLD through a mechanism that is poorly understood. We adopted a proteomic approach to examine the effect of HFD on the liver proteome during the progression of NAFLD. Male Sprague‐Dawley rats fed an HFD for 4, 12, and 24 weeks replicated the progression of human NAFLD: steatosis, nonspecific inflammation, and steatohepatitis. Using two‐dimensional difference gel electrophoresis (DIGE) combined with matrix‐assisted laser desorption ionization time of flight/time of flight analysis, 95 proteins exhibiting significant changes (ratio ≥ 1.5 or ≤−1.5, P < 0.05) during the development of NAFLD were identified. Biological functions for these proteins reflected phase‐specific characteristics during the progression of the disease. The potential role of enoyl–coenzyme A hydratase (ECHS1), an enzyme that catalyzes the second step of mitochondrial fatty acid beta‐oxidation, received further investigation. First, the reduced protein level of ECHS1 was validated both in rat models and in patients with biopsy‐proven hepatic simple steatosis via immunoblotting or immunohistochemical analysis. Then the small interfering RNA (siRNA)–mediated knockdown of ECHS1 in the murine hepatocyte cell line alpha mouse liver 12 (AML12) demonstrated increased cellular lipid accumulation induced by free fatty acid (FFA) overload. Furthermore, using a hydradynamic transfection method, the in vivo silencing effect of siRNA duplexes targeting ECHS1 was further investigated in mice. Administering ECHS1 siRNA specifically reduced the expression of ECHS1 protein in mice liver, which significantly exacerbated the hepatic steatosis induced by an HFD. Conclusion: Our results revealed that ECHS1 down‐regulation contributed to HFD‐induced hepatic steatosis, which may help clarify the pathogenesis of NAFLD and point to potential targets for therapeutic interventions. (HEPATOLOGY 2010.)

Liverbase: a comprehensive view of human liver biology.

The Liverbase ( http://liverbase.hupo.org.cn ) integrates information on the human liver proteome, including the function, abundance, and subcellular localization of proteins as well as associated disease information. The overall objective of the Liverbase is to provide a unique public resource for the liver community by providing comprehensive functional annotation of proteins implicated in liver development and disease. The central database features are manually annotated proteins localized in or functionally associated with human liver. In this first version of Liverbase, the associated data includes the human liver proteome (6788 proteins) and transcriptome (11205 significantly expressed genes: 10224 from CHIP and 5422 from MPSS, respecively) from the Chinese human liver proteome project (CNHLPP). As a database made publicly available through the Web site, Liverbase provides browsing and searching capabilities and a compilation of external links to other databases and homepages. Liverbase enables (i) the establishment of liver GO slim with 51 nonredundant items; (ii) systematic searches for proteins within specific functional or metabolic pathways; (iii) systematic searches that aim to find the proteins that underlie common and rare liver diseases; and (iv) the integration of detailed protein annotations derived from the literature. Liverbase also contains an external links page with links to other biological databases and homepages, including GO, KEGG, pfam, SWISS-PROT, and GNF databases. Liverbase users can utilize all these information to conduct systems biology research on liver.

Association between serum growth hormone levels and nonalcoholic fatty liver disease: a cross-sectional study.

Growth hormone (GH) is an important regulator of metabolism and body composition. GH deficiency is associated with increased visceral body fat and other features of the metabolic syndrome. Here we performed a cross-sectional study to explore the association of GH levels with nonalcoholic fatty liver disease (NAFLD), which is considered to be the hepatic manifestation of the metabolic syndrome. A total of 1,667 subjects were diagnosed as NAFLD according the diagnostic criteria, and 5,479 subjects were defined as the controls. The subjects with NAFLD had significantly lower levels of serum GH than the controls. Those with low GH levels had a higher prevalence of NAFLD and the metabolic syndrome. A stepwise logistic regression analysis showed that GH levels were significantly associated with the risk factor for NAFLD (OR = 0.651, 95%CI = 0.574–0.738, P<0.001). Our results showed a significant association between lower serum GH levels and NAFLD.

Relationships between Hematopoiesis and Hepatogenesis in the Midtrimester Fetal Liver Characterized by Dynamic Transcriptomic and Proteomic Profiles

In fetal hematopoietic organs, the switch from hematopoiesis is hypothesized to be a critical time point for organogenesis, but it is not yet evidenced. The transient coexistence of hematopoiesis will be useful to understand the development of fetal liver (FL) around this time and its relationship to hematopoiesis. Here, the temporal and the comparative transcriptomic and proteomic profiles were observed during the critical time points corresponding to the initiation (E11.5), peak (E14.5), recession (E15.5), and disappearance (3 ddp) of mouse FL hematopoiesis. We found that E11.5-E14.5 corresponds to a FL hematopoietic expansion phase with distinct molecular features, including the expression of new transcription factors, many of which are novel KRAB (Kruppel-associated box)-containing zinc finger proteins. This time period is also characterized by extensive depression of some liver functions, especially catabolism/utilization, immune and defense, classical complement cascades, and intrinsic blood coagulation. Instead, the other liver functions increased, such as xenobiotic and sterol metabolism, synthesis of carbohydrate and glycan, the alternate and lectin complement cascades and extrinsic blood coagulation, and etc. Strikingly, all of the liver functions were significantly increased at E14.5-E15.5 and thereafter, and the depression of the key pathways attributes to build the hematopoietic microenvironment. These findings signal hematopoiesis emigration is the key to open the door of liver maturation.

Proteomic analysis of hepatic ischemia/reperfusion injury and ischemic preconditioning in mice revealed the protective role of ATP5β

Hepatic ischemia/reperfusion (I/R) injury is an inevitable consequence during liver surgery. Ischemic preconditioning (IPC) has been shown to protect the livers from I/R injury, partially mediated by preservation of hepatic ATP contents. However, the precise molecular mechanisms of these events remain poorly elucidated. In this study, liver proteomes of the mice subjected to I/R injury pretreated with or without IPC were analyzed using 2‐DE combined with MALDI‐TOF/TOF mass analysis. Twenty proteins showing more than 1.5‐fold difference were identified in the livers upon I/R injury. Among these proteins, four proteins were further regulated by IPC when compared with nonpretreated controls. One of these proteins, ATP synthase β subunit (ATP5β) catalyzes the rate‐limiting step of ATP formation. The expression level of ATP5β, which was further validated by Western blot analysis, was significantly decreased upon I/R injury while turned over by IPC pretreatment. Change pattern of hepatic ATP corresponded with that of ATP5β expression, indicating that increasing hepatic ATP5β expression might be a reason for ATP‐preserving effect of IPC. In summary, this study provided new clues for understanding the mechanisms of IPC against I/R injury. The protective role of ATP5β might give evidences for developing new therapeutic approaches against hepatic I/R injury.

Influences of sub-Alfvenic shear flows on nonlinear evolution of magnetic reconnection in compressible plasmas

Influences of sub-Alfvenic shear flows on the nonlinear evolution of the magnetic reconnection are studied in the framework of compressible resistive MHD and compressible Hall MHD. It is found for the first time that the sub-Alfvenic shear flow can either stabilize or destabilize magnetic reconnection, which is mainly determined by the plasma beta and the half thickness of the shear flow ( λ v ). The shear flow exhibits a suppressing effect on magnetic reconnection and the boosting effect nearly disappears for the beta plasma β ≲ 1 , which is associated with the presence of a pair of discontinuities in the upper and lower inflow region. The shear flow has the boosting effect on magnetic reconnection when the half thickness of the shear flow exceeds a critical value in the high beta plasma which is in a good agreement with the results from incompressible simulation. With the inclusion of the Hall effect,shear flow can still either stabilize or destabilize magnetic reconnection, but the boosting effect becomes weaker as the ion inertial length d i increases.

A role of microRNA-370 in hepatic ischaemia-reperfusion injury by targeting transforming growth factor-β receptor II

MicroRNAs (miRNAs) are a group of small non‐coding RNAs with modulator activity of gene expression. The role of miRNAs in hepatic ischaemia‐reperfusion (IR) injury is currently largely unknown. The aim of this study was to investigate the potential role of miR‐370 in hepatic IR injury.

PDIA3 Knockdown Exacerbates Free Fatty Acid-Induced Hepatocyte Steatosis and Apoptosis.

Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most common chronic liver disease over the past decades. Endoplasmic reticulum stress (ERS) plays a pivotal role during the development of NAFLD. This study aims to analyze the potential role of protein disulfide isomerase A3 precursor (PDIA3), one of the ER chaperones, in free fatty acid-induced cell model of NAFLD. Human liver L02 cell line was treated with sodium palmitate for 24 hours, which developed severe intracellular lipid accumulation. The increased protein level of PDIA3 was detected via immunoblotting analysis in the fat loaded cell models of NAFLD. siRNA-mediated knockdown of PDIA3 in L02 cells not only increased the cellular lipid accumulation, but also exacerbated hepatocytes apoptosis induced by sodium palmitate. Further investigation revealed that knockdown of PDIA3 up-regulated protein expression of fatty acid synthase (FAS), a key enzyme involved in fatty acid synthesis. PDIA3 knockdown also up-regulated key molecules of ERS pathway, including glucose-regulated protein 78 (GRP78), phospho-PKR-like ER kinase (p-PERK), and C/EBP homologous protein (CHOP). Our results suggested that ER chaperone PDIA3 plays a pivotal role in FFA-induced hepatocyte steatosis and apoptosis.

High-resolution electron energy loss spectroscopy and angle-resolved ultra-violet photoemission spectroscopy studies of carbon monoxide on a Cs-precovered surface

There are two molecular adsorption states of CO in the system. One is , with lower C - O frequency, and the other is , with higher C - O frequency. The latter is similar to that on a clean surface. The two states of CO are occupied sequentially during the exposure to CO. The C - O stretch frequency of both states shifts to a higher value with the exposure to CO and to a lower value with higher Cs precoverage. The electronic structure of the molecule is different from that of the molecule and is of the same character as CO in a tilted mode.